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Screening a library of drugs with known safety profiles in humans yielded 30 drugs that reliably protected mammalian neurons against glucose toxicity. Subsequent screening demonstrated that 6 of these 30 drugs increase lifespan in C. elegans: caffeine, ciclopirox olamine, tannic acid, acetaminophen, bacitracin, and baicalein. Every drug significantly reduced the age-dependent acceleration of mortality rate. These protective effects were blocked by RNAi inhibition of cbp-1 in adults only, which also blocks protective effects of dietary restriction. Only 2 drugs, caffeine and tannic acid, exhibited a similar dependency on DAF-16. Caffeine, tannic acid, and bacitracin also reduced pathology in a transgenic model of proteotoxicity associated with Alzheimer's disease. These results further support a key role for glucose toxicity in driving age-related pathologies and for CBP-1 in protection against age-related pathologies. These results also provide novel lead compounds with known safety profiles in human for treatment of age-related diseases, including Alzheimer's disease and diabetic complications.

Several classes of immunomodulators are used for treating relapsing-remitting multiple sclerosis (RRMS). Most of these disease-modifying therapies, except teriflunomide, carry the risk of progressive multifocal leukoencephalopathy (PML), a severely debilitating, often fatal virus-induced demyelinating disease. Because teriflunomide has been shown to have antiviral activity against DNA viruses, we investigated whether treatment of cells with teriflunomide inhibits infection and spread of JC polyomavirus (JCPyV), the causative agent of PML. Treatment of choroid plexus epithelial cells and astrocytes with teriflunomide reduced JCPyV infection and spread. We also used droplet digital PCR to quantify JCPyV DNA associated with extracellular vesicles isolated from RRMS patients. We detected JCPyV DNA in all patients with confirmed PML diagnosis (n = 2), and in six natalizumab-treated (n = 12), two teriflunomide-treated (n = 7), and two nonimmunomodulated (n = 2) patients. Of the 21 patients, 12 (57%) had detectable JCPyV in either plasma or serum. CSF was uniformly negative for JCPyV. Isolation of extracellular vesicles did not increase the level of detection of JCPyV DNA versus bulk unprocessed biofluid. Overall, our study demonstrated an effect of teriflunomide inhibiting JCPyV infection and spread in glial and choroid plexus epithelial cells. Larger studies using patient samples are needed to correlate these in vitro findings with patient data.

Chronic treatment with β-adrenergic receptor (βAR) agonists increases mortality and morbidity while βAR antagonists (β-blockers) decrease all-cause mortality for those at risk of cardiac disease. Levels of sympathetic nervous system βAR agonists and βAR activity increase with age, and this increase may hasten the development of age-related mortality. Here, we show that β-blockers extend the life span of healthy metazoans. The β-blockers metoprolol and nebivolol, administered in food daily beginning at 12 months of age, significantly increase the mean and median life span of isocalorically fed, male C3B6F1 mice, by 10 and 6.4 %, respectively ( P  < 0.05). Neither drug affected the weight or food intake of the mice, indicating that induced CR is not responsible for these effects, and that energy absorption and utilization are not altered by the drugs. Both β-blockers were investigated to control for their idiosyncratic, off-target effects. Metoprolol and nebivolol extended Drosophila life span, without affecting food intake or locomotion. Thus, βAR antagonists are capable of directly extending the life span of two widely divergent metazoans, suggesting that these effects are phylogenetically highly conserved. Thus, long-term use of β-blockers, which are generally well-tolerated, may enhance the longevity of healthy humans.

Chronic treatment with [beta]-adrenergic receptor ([beta]AR) agonists increases mortality and morbidity while [beta]AR antagonists ([beta]-blockers) decrease all-cause mortality for those at risk of cardiac disease. Levels of sympathetic nervous system [beta]AR agonists and [beta]AR activity increase with age, and this increase may hasten the development of age-related mortality. Here, we show that [beta]-blockers extend the life span of healthy metazoans. The [beta]-blockers metoprolol and nebivolol, administered in food daily beginning at 12 months of age, significantly increase the mean and median life span of isocalorically fed, male C3B6F1 mice, by 10 and 6.4 %, respectively (P<0.05). Neither drug affected the weight or food intake of the mice, indicating that induced CR is not responsible for these effects, and that energy absorption and utilization are not altered by the drugs. Both [beta]-blockers were investigated to control for their idiosyncratic, off-target effects. Metoprolol and nebivolol extended Drosophila life span, without affecting food intake or locomotion. Thus, [beta]AR antagonists are capable of directly extending the life span of two widely divergent metazoans, suggesting that these effects are phylogenetically highly conserved. Thus, long-term use of [beta]-blockers, which are generally well-tolerated, may enhance the longevity of healthy humans. [PUBLICATION ABSTRACT]

In C. elegans, Notch/GLP-1 is vital to both germ cell and embryonic development. The glp-1 mRNA is translationally regulated in the germline and embryo to localize Notch signaling to specific cells at specific times of development. However, little is known about the factors that control glp-1 translation. To find genes that regulate glp-1, we used RNA interference to screen a library of genes shown by microarray analysis to have increased expression in the germline. From these germline-enriched genes, 97 were selected that encode potential RNA binding proteins. RNAi of these 97 genes identified a single candidate, puf-5, that represses GLP-1 expression in oocytes. PUF-5 protein is related to the Pumilio and FBF family of proteins, several of which control mRNA translation or stability in various organisms. Following puf-5 RNAi, GLP-1 expression was de-repressed in late-stage oocytes from early diakinesis to immediately before oocyte maturation. In other regions of puf-5(RNAi) germlines and embryos, GLP-1 regulation was largely unaffected. In addition, we found that three nearly identical PUF proteins, PUF-6, PUF-7, and PUF-10, but not other PUF proteins, also were required for glp-1 repression in oocytes. Loss of PUF-5 or PUF-6/7/10 also caused defects in oogenesis. Furthermore, PUF-5 protein was detected in late stage oocytes by immunofluorescence, but was not detectable in early stage germ cells of the distal gonad arm. Recombinant PUF-5 and PUF-6 bound weakly but specifically to a small region of the glp-1 3′ UTR in vitro. However, it is not yet known if direct binding to glp-1 mRNA is important for translational control in vivo. These studies, together with previous work, suggest that distinct RNA binding complexes repress maternal mRNA translation at different stages of germ cell development. The KH protein GLD-1 represses several mRNAs including glp-1 during early oogenesis, while PUF-5, PUF-6, PUF-7, and PUF-10 are key components of a regulatory system that represses Notch/glp-1 and probably other maternal mRNAs during late oogenesis.

Mr. Dunlap's blitzkrieg didn't stop there. In a year, he engineered one of the fastest turnarounds in corporate history -- an effort capped last week by Kimberly-Clark Corp.'s $7.36 billion offer for Scott. But the difficulty of turning a company around at all, let alone fast, shouldn't be underestimated. In January, turnaround specialist C. Robert Kidder became the fourth chief of Borden Inc. since 1986. Four months later, he unveiled a \"realignment\" -- the fifth restructuring in six years for the Columbus, Ohio, food and chemical conglomerate. When will Borden finally turn around? \"We're working on it,\" a spokesman says. In each case, a corporate crisis compelled a new leader to move swiftly. Scott lost $277 million in 1993. Compaq posted its first quarterly loss ever in autumn 1991, ousted its founder and promoted Eckhard Pfeiffer to CEO. GM took a $744 million fourth-quarter charge in 1992 due to its National losses; it hired turnaround expert Jay Alix in January 1993.

Spinal cord involvement is an important cause of disability in patients with multiple sclerosis or neuromyelitis optica spectrum disorders (NMOSDs). Multiple sclerosis and NMOSDs can be distinguished from other disorders that cause myelopathy by results from laboratory and radiological investigations. However, limitations in the sensitivity and specificity of spinal cord imaging and poor correlation with disability megasures have impeded the understanding of the relationship between spinal cord involvement and clinical manifestations. Nevertheless, studies of the pathological features of multiple sclerosis and NMOSDs have shown that quantitatively different mechanisms lead to differences in clinical course and pattern of accrual of permanent disability in the two disorders. Better understanding of these mechanisms is necessary to develop more informative clinical measures, electrophysiological methods, fluid biomarkers, and imaging techniques to detect and monitor spinal cord involvement in the diagnosis and management of patients with multiple sclerosis or NMOSDs, and as outcome measures in clinical trials.

\"The days of the conglomerate or the highly diversified company may be passing,\" says David Nadler, chairman of Delta Consulting Group Inc. in New York. He attributes current break-up fever to \"a fundamental restructuring of the portfolios of corporate America as they search for real versus illusory value.\" He adds: \"We will see more of this.\" Businesses' race to skinny down and focus on a few core strengths has created nearly 100 newly spunoff companies since 1992, according to a study by J.P. Morgan & Co. and Securities Data Corp. Combined with AT&T's break-up announcement and a slew of pending spinoffs, the trend has added nearly $100 billion to corporate war chests -- money that's often used to finance future acquisitions. Feeding the mania are tax advantages and a surging stock market that laps up spinoff news as well as new offerings. ITT Corp.'s stock has risen about 16% since its June 13 announcement of plan to divide the conglomerate into three new, separately traded concerns. ITT investors are expected to approve the plan at a special meeting today. Sears, Robuck & Co., General Motors Corp. and Viacom Inc. have also enjoyed run-ups in their share prices following spinoff announcements or completions this summer.

Del Wallick wears his pride under his sleeve. A handshake reveals his prized wristwatch, given to mark his 25th anniversary with Timken Co. \"I only take it off to shower and sleep,\" he says. The hallways of Mr. Wallick's home in Canton, Ohio, are filled with an array of certificates marking the milestones in his 31-year career as a Timken steel-mill worker. Down in his recreation room, a mantel clock that he and his wife picked out from a Timken gift catalog rests atop the family television set. The roster of companies reducing or eliminating longevity-reward programs in recent years includes some well-known names: International Business Machines Corp., Scott Paper Co., Merck & Co. and American Express Co. According to an American Management Association survey conducted for The Wall Street Journal, 14.2% of the 522 responding companies that reward, or once rewarded, longevity either reduced or eliminated such programs in the past five years.

Breakups enable companies to jettison historically troubled divisions and raise cash for new strategies. Also feeding the breakup mania are tax advantages and a surging stock market that laps up spinoff news as well as new offerings. At a time when chief executives are increasingly judged by their companies' stock performance, the stock-price surges that often result make spinoffs tempting. ITT Corp.; Sears, Roebuck and Co.; General Motors Corp.; and Viacom Inc. have had run-ups in their share prices after spinoff announcements or completions this summer.